scholarly journals Phosphorylation Mechanism of Phosphomevalonate Kinase: Implications for Rational Engineering of Isoprenoid Biosynthetic Pathway Enzymes

2016 ◽  
Vol 120 (41) ◽  
pp. 10714-10722 ◽  
Author(s):  
Meilan Huang ◽  
Kexin Wei ◽  
Xiao Li ◽  
James McClory ◽  
Guixiang Hu ◽  
...  
Keyword(s):  
Biosynthetic Pathway ◽  
Rational Engineering ◽  
Phosphorylation Mechanism ◽  
Phosphomevalonate Kinase ◽  
Isoprenoid Biosynthetic Pathway

scholarly journals Effects of Farnesyl Pyrophosphate Accumulation on Calvarial Osteoblast Differentiation

Endocrinology ◽  
2011 ◽  
Vol 152 (8) ◽  
pp. 3113-3122 ◽  
Author(s):  
Megan M. Weivoda ◽  
Raymond J. Hohl
Keyword(s):  
Bone Formation ◽  
Osteoblast Differentiation ◽  
Biosynthetic Pathway ◽  
Squalene Synthase ◽  
Farnesyl Pyrophosphate ◽  
Matrix Mineralization ◽  
Lower Serum Cholesterol ◽  
Calvarial Osteoblast ◽  
Isoprenoid Biosynthetic Pathway

Statins, drugs commonly used to lower serum cholesterol, have been shown to stimulate osteoblast differentiation and bone formation. Statins inhibit 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A reductase (HMGCR), the first step of the isoprenoid biosynthetic pathway, leading to the depletion of the isoprenoids farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). The effects of statins on bone have previously been attributed to the depletion of GGPP, because the addition of exogenous GGPP prevented statin-stimulated osteoblast differentiation in vitro. However, in a recent report, we demonstrated that the specific depletion of GGPP did not stimulate but, in fact, inhibited osteoblast differentiation. This led us to hypothesize that isoprenoids upstream of GGPP play a role in the regulation of osteoblast differentiation. We demonstrate here that the expression of HMGCR and FPP synthase decreased during primary calvarial osteoblast differentiation, correlating with decreased FPP and GGPP levels during differentiation. Zaragozic acid (ZGA) inhibits the isoprenoid biosynthetic pathway enzyme squalene synthase, leading to an accumulation of the squalene synthase substrate FPP. ZGA treatment of calvarial osteoblasts led to a significant increase in intracellular FPP and resulted in inhibition of osteoblast differentiation as measured by osteoblastic gene expression, alkaline phosphatase activity, and matrix mineralization. Simultaneous HMGCR inhibition prevented the accumulation of FPP and restored osteoblast differentiation. In contrast, specifically inhibiting GGPPS to lower the ZGA-induced increase in GGPP did not restore osteoblast differentiation. The specificity of HMGCR inhibition to restore osteoblast differentiation of ZGA-treated cultures through the reduction in isoprenoid accumulation was confirmed with the addition of exogenous mevalonate. Similar to ZGA treatment, exogenous FPP inhibited the mineralization of primary calvarial osteoblasts. Interestingly, the effects of FPP accumulation on osteoblasts were found to be independent of protein farnesylation. Our findings are the first to demonstrate that the accumulation of FPP impairs osteoblast differentiation and suggests that the depletion of this isoprenoid may be necessary for normal and statin-induced bone formation.

Reconstruction of a bacterial isoprenoid biosynthetic pathway inSaccharomyces cerevisiae

FEBS Letters ◽  
2008 ◽  
Vol 582 (29) ◽  
pp. 4032-4038 ◽  
Author(s):  
Jérôme Maury ◽  
Mohammad A. Asadollahi ◽  
Kasper Møller ◽  
Michel Schalk ◽  
Anthony Clark ◽  
...  
Keyword(s):  
Biosynthetic Pathway ◽  
Isoprenoid Biosynthetic Pathway

scholarly journals Localization of the pre-squalene segment of the isoprenoid biosynthetic pathway in mammalian peroxisomes

2006 ◽  
Vol 127 (3) ◽  
pp. 273-290 ◽  
Author(s):  
Werner J. Kovacs ◽  
Khanichi N. Tape ◽  
Janis E. Shackelford ◽  
Xueying Duan ◽  
Takhar Kasumov ◽  
...  
Keyword(s):  
Biosynthetic Pathway ◽  
Isoprenoid Biosynthetic Pathway
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